CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation
Frederick J. Sheedy,Alena Grebe,Katey J. Rayner,Parisa Kalantari,Bhama Ramkhelawon,Susan Carpenter,Christine Becker,Hasini Ediriweera,Adam E. Mullick,Douglas T. Golenbock,Lynda M. Stuart,Eicke Latz,Eicke Latz,Eicke Latz,Katherine A. Fitzgerald,Kathryn J. Moore +15 more
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TLDR
This work identifies an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome in sterile inflammation.Abstract:
Particulate ligands, including cholesterol crystals and amyloid fibrils, induce production of interleukin 1β (IL-1β) dependent on the cytoplasmic sensor NLRP3 in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands, including oxidized low-density lipoprotein (LDL), amyloid-β and amylin peptides, accumulate in such diseases. Here we identify an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of those soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome. Consequently, macrophages that lacked CD36 failed to elicit IL-1β production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1β and accumulation of cholesterol crystals in plaques. Collectively, our findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation.read more
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References
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TL;DR: It is shown that cell priming through multiple signaling receptors induces NLRP3 expression, which is identified to be a critical checkpoint for NLRP2 activation and signals provided by NF-κB activators are necessary but not sufficient forNLRP3 activation.
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